Design, synthesis and evaluation the bioactivities of novel 8‑methoxy-1-azacoumarin-3-carboxamide derivatives as anti-diabetic agents

Abstract

In this study, a novel series of 8‑methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid and N-substituted 8‑methoxy-2-oxo-1,2-dihydroquinoline-3-carboxamide derivatives 2–10 were designed, synthesized, and screened for their in vitro α-amylase, α-glucosidase and DPP-4 enzymes resulting in effective anti-diabetic agents. The research results showed that these compounds had significant inhibitory effects on both α-amylase and α-glucosidase enzymes. Specifically, compound 4 demonstrated the most potency with IC50 of 30.50±2.67 and 19.98±3.24µM for α-glucosidase and α-amylase activities respectively, which was significantly more powerful than the drug Acarbose (IC50 = 48.97±3.42µM and 16.59±3.78µM). Also, compound 4 Exhibits strong inhibitory activity against DPP-4 with an IC50 value of 0.035±6.65nM as compared to the positive control sitagliptin (IC50 =0.014±6.91nM).Also, we had performed the kinetic study for the most potent compound 4 on α-amylase and α-glucosidase enzymes to study the type of inhibition of enzymes. The results showed that compound 4 was non-competitive inhibitor that can bind to an enzyme at a site other than the active site, known as the allosteric site. Investigating the potential of compound 4 to treat diabetes, we evaluated its cytotoxic and antioxidant properties. Our results indicated that it had a highly effective scavenging ability for DPPH with an IC50 value of 15.45±3.83µM, outperforming ascorbic acid (IC50 =7.24±8.01µM), the positive control. Exhilarated by these promising findings, we continue to explore the varied possibilities for these compounds.